Cardiovascular disease remains a leading cause of mortality in the developed world1,2. In particular, chronic heart failure (HF) continues to represent an enormous clinical challenge since HF mortality and incidence continue to rise2,3. Although pharmacological therapy has considerably improved HF care over the last two decades, existing treatments are not ideal since they often fail to support myocardium and increase global cardiac function1-3. Therefore, novel therapeutic approaches to target the underlying molecular defects of ventricular dysfunction in HF are needed. One hallmark molecular defect in failing myocardium is dysfunctional intracellular calcium (Ca2+) handling and several Ca2+-cycling proteins have been identified as potential targets for reversing failing myocyte function4,5.
S100A1 is a low molecular weight (˜10 kDa) Ca2+-sensing protein of the EF-hand type known to modulate intracellular calcium [Ca2+]i-handling in various cell types such as neurons, skeletal muscle and cardiomyocytes.7,14,38-39 Several biological activities such as the regulation of myocardial- and skeletal muscle contractility, cytoskeleton-mediated interactions, apoptosis, regulation of metabolic enzymes, proliferation and cell differentiation are affected by S100A1 mediated alterations in [Ca2+]i.40-42 S100A1 is especially interesting with respect to cardiovascular diseases since cardiac S100A1 expression levels are significantly down-regulated in end-stage heart failure (HF). S100A1 is a positive inotropic regulator of myocardial function in vitro and in vivo6-10. This effect is mainly mediated by a significant gain in sarcoplasmic reticulum (SR) Ca2+-cycling.13,14 Consistent with S100A1 being a key player in cardiac contractile function, data generated from S100A1 knock-out mice demonstrate that the loss of S100A1 expression leads to an inability of the heart to adapt to acute or chronic hemodynamic stress in vivo11,12. Importantly, S100A1 mediated affects on cardiac contractile function do not interfere with basic regulatory mechanisms of myocardial contractility9 and have been found to be independent of β-adrenergic signaling7. Functional properties of S100A1 in cardiomyocytes are mainly caused by increased sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a) activity, diminished diastolic SR Ca2+-leak and augmented systolic open probability of the ryanodine receptor (RyR) causing an overall significant gain in SR Ca2+-cycling13-15. This demonstrates a potential distinct mechanism of action for S100A1 altering Ca2+-handling in both phases of SR function.
Recently S100A1 expression has been described in endothelial cells (EC).43 EC synthesize and release vasoactive mediators in response to neurohumoural and physical stimuli, thus playing an important role in the regulation of vascular function. A well characterized and critical regulator of endothelial function is nitric oxide (NO) which is generated by endothelial NO synthase (eNOS or NOS3).44 Importantly, activation of eNOS is classically dependent on increased [Ca2+]i which can be induced by agonists such as acetylcholine (ACh) or bradykinin.45,46 NO contributes to endothelium-dependent vascular relaxation and has additional functional roles such as anti-leukocyte adhesion, anti-proliferative and anti-apoptotic effects on the vascular wall.45,47 Loss of endothelial NO results in endothelial dysfunction which occurs in a variety of cardiovascular diseases and is associated with adverse effects such as vascular inflammation, impaired vascular function and long-term vascular remodeling.48 Moreover, recent data provide evidence that endothelial dysfunction in HF is also associated with an increased mortality risk in patients with both ischemic and non-ischemic HF.49 
Since S100A1 play a significant role of in the regulation of [Ca2+]i-transients in various cell types7, 14, 38-39, and it being highly and preferentially expressed in the healthy heart while it is found to be significantly down-regulated in HF16, it would appear that S100A1 is important in HF. Accordingly, a method of chronic S100A1 gene delivery to failing myocardium can be used to improve SR Ca2+-signaling and to support contractile function in HF. However, before this potential target as well as others for HF gene therapy are realized17, safe, efficient and reproducible gene therapy vector systems must be established and tested. It is becoming increasingly clear that recombinant adeno-associated viral (rAAV) vectors have properties amenable to future human use and S100A1 delivered to myocardium using these vectors may indeed fulfill the currently unmet promise of HF gene therapy.